The present invention relates to a combination of a thiazolidinedione (TZD), with glucagon-like peptide-1 (GLP-1) or a GLP-1 agonist, which combination possesses desirable hormonal activity and can be used to regulate glucose homeostasis in patients suffering from non-insulin dependent diabetes mellitus (Type II diabetes).
Insulin resistance is a classic feature of many human disease conditions, such as Non-Insulin-Dependent Diabetes Mellitus (NIDDM), obesity, hypertension, aging, etc. Diabetes mellitus is a disorder of carbohydrate metabolism, characterized by hyperglycemia and glycosuria resulting from inadequate production or utilization of insulin. NIDDM is a form of diabetes where utilization of insulin is inadequate. It occurs predominantly in adults, in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose and peripheral tissues. For some people with diabetes, a mutation in the gene(s) coding for insulin, for insulin receptor and/or for insulin-mediated signal transduction factor(s) leads to ineffective insulin and/or insulin-mediated effects, impairing the utilization or metabolism of glucose.
Diabetes mellitus often develops from certain at risk populations; it is known that one such population is individuals with impaired glucose tolerance (IGT). The usual meaning of impaired glucose tolerance is that it is a condition intermediate between frank, non-insulin-dependent diabetes mellitus and normal glucose tolerance. IGT is diagnosed by a procedure wherein an affected person's postprandial glucose response is determined to be abnormal as assessed by two-hour postprandial plasma glucose levels. In this test, a measured amount of glucose is given to the patient and blood glucose level measured at regular intervals, usually every ½ hour for the first two hours and every hour thereafter. In a “normal” or non-IGT individual, glucose levels rise during the first two hours to a level less than 140 mg/dl and then drop rapidly. In an impaired individual (IGT) the blood glucose levels are higher and the dropoff level is at a slower rate. A high percentage of the impaired (IGT) population is known to progress to non-insulin dependent diabetes mellitus.
The pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM) consists of three major components, (1) peripheral insulin resistance; (2) increased hepatic glucose production; and (3) impaired insulin secretion. Intense research has been devoted to each of these areas, independently, in order to determine which abnormality is primary and which are secondary. The prevailing view is that a rational therapeutic pharmacological approach should involve intervention in the insulin resistance to improve glucose homeostasis. Suter et al., Diabetes Care 15: 193–203 (1992). As a result of the focus on individual abnormalities, several model therapies were developed to regulate glucose homeostasis in Type II diabetic patients.
When focussing on peripheral insulin resistance, the drug of choice is a thiazolidinedione, which is a type of insulin-sensitizing agent. Troglitazone (TRG), for example, is an orally active anti-diabetic agent of the thiazolidinedione chemical series. This drug has been shown to reverse insulin resistance in patients with NIDDM and impaired glucose tolerance, and can enhance insulin action in numerous genetic and acquired rodent models of insulin resistance. The antihyperglycemic effects of TRG result from its ability to increase insulin dependent glucose disposal and reduce hepatic glucose production. It is believed, by enhancing insulin action, TRG treatment results in euglycemia at a lower circulating insulin level. In this regard, studies in normal and diabetic rodents and human clinical trials have not revealed hypoglycemia as a complication of thiazolidinedione therapy. On the other hand, administration of these drugs to normal or insulin-deficient diabetic animals failed to alter plasma glucose or insulin or glucose tolerance, although insulin sensitivity was nevertheless increased.
The effects of TRG and other thiazolidinediones on glucose disposal are thought to result from insulin sensitization, indicating an absolute requirement for insulin. On the other hand, TRG does improve insulin sensitivity as assessed by the hyperinsulinemic clamp. Suter et al., supra. Dose-dependent effects of thiazolidinediones on plasma insulin and glucose tolerance have been demonstrated in mouse and rat models other than the GK rat model.
Inhibiting gluconeogenesis in vivo would result in a decrease in glycogen stores. Following TRG treatment, we presumably begin with a smaller amount of glycogen and therefore show a decrease in total hepatic glucose output. It is also possible that TRG has a direct effect on the glycogenolitic pathway. The exact biochemical mechanism responsible for this effect is still under investigation. In vivo and ex vivo data in the GK rat further support the possibility that the effects of this drug on liver and peripheral tissue may be independent and different in some respects.
Thiazolidinedione treatments are based on the assumption that if you focus on peripheral insulin resistance, increased hepatic glucose production and impaired insulin secretion will be alleviated in due course. Additionally, determining the optimal dose of TZD for increasing insulin sensitivity has been a difficult undertaking. There is an additional dilemma that, even at the optimum dose, TZD monotherapy causes heart hypertrophy in animal models. Smits et al., Diabetologia 38:116–121 (1995). This side effect renders TZD monotherapy an undesirable prophylactic measure in the treatment of Type II diabetes mellitus.
The other primary approach to treating Type II diabetes mellitus focuses on facilitating insulin secretion, using insulin secretion-potentiating agents. The endocrine secretions of the pancreatic islets are under complex control not only by blood-borne metabolites (glucose, amino acids, catecholamines, etc.), but also by local paracrin influences. The major pancreatic islet hormones (glucagon, insulin and somatostatin) interact amongst their specific cell types (A, B and D cells, respectively) to modulate secretory responses mediated by the aforementioned metabolites. Although insulin secretion is predominantly controlled by blood levels of glucose, somatostatin inhibits glucose-mediated insulin secretory responses. In addition to the proposed inter-islet paracrin regulation of insulin secretion, there is evidence to support the existence of insulinotropic factors in the intestine. For example, glucose taken orally is a much more potent stimulant of insulin secretion than is a comparable amount of glucose given intravenously.
By focussing primarily on secretion of endogenous insulin, this method relies on the assumption that peripheral insulin resistance and increased hepatic glucose production would be regulated by insulin secretion treatments alone. However, of equal importance to the effective treatment of non-insulin diabetes mellitus is insulin sensitization which is the promotion of glucose utilization by enhanced insulin action. Increasing insulin secretion and/or synthesis without decreasing insulin resistance has little effect on glucose utilization.
Attempts to address the multiple abnormalities associated with non-insulin dependent diabetes mellitus have called for the co-administration of GLP-1 in conjunction with glibenclamide, which is a sulphonylurea. See U.S. Pat. No. 5,631,224. Sulphonylurea derivatives stimulate insulin secretion without an effect on insulin synthesis. Sulphonylureas act by closure of ATP-dependent potassium channels and pancreatic beta-cells. This leads to depolarization of the plasma membranes with opening of voltage-dependent calcium channels with inflow of calcium ions. Calcium ions bind to calmodulin, leading to activation of insulin exocytosis in a similar manner to that found after stimulation with glucose. In contrast to earlier beliefs, some sulphonylureas, such as glibenclamide, may interact with human vascular ATP-dependent channels. This may have consequences for vascular responses during ischaemia, which are, at least in part, mediated by ATP-dependent potassium channels.
During ischaemia in experimental animals, it has been suggested that shortening of the action potential exerts a protection effect, thereby reducing contractility, oxygen demand and repercussion damage. Under these circumstances sulphonylureas such as glibenclamide may inhibit potassium channels in the ischaemic myocardium, and so prevent the shortening of the action potential. This may result in less coronary vasodilation, more tissue damage and more reperfusion arrhythmias.
In light of heart hypertrophy, which is a side effect of TZD and increased tissue damage resulting from sulphonylurea administration, a new approach to treating type II diabetes mellitus is needed. The new approach should be a multi-pronged approach to the pathophysiology of NIDDM, which is not limited to the treatment of only peripheral insulin resistance, or only impaired insulin secretion. The appropriate treatment would ameliorate peripheral insulin resistance, increase hepatic glucose production, and facilitate insulin secretion without heart hypertrophy and increased tissue damage.